Comparative Genomics within and across Bilaterians Illuminates the Evolutionary History of ALK and LTK Proto-Oncogene Origination and Diversification

Comparative genomic analyses have enormous potential for identifying key genes central to human health phenotypes, including those that promote cancers. In particular, the successful development of novel therapeutics using model species requires phylogenetic analyses to determine molecular homology. Accordingly, we investigate the evolutionary histories of anaplastic lymphoma kinase (ALK)-which can underlie tumorigenesis in neuroblastoma, nonsmall cell lung cancer, and anaplastic large-cell lymphomaits close relative leukocyte tyrosine kinase (LTK) and their candidate ligands. Homology of ligands identified in model organisms to those functioning in humans remains unclear. Therefore, we searched for homologs of the human genes across metazoan genomes, finding that the candidate ligands Jeb and Hen-1 were restricted to nonvertebrate species. In contrast, the ligand augmentor (AUG) was only identified in vertebrates. We found two ALK-like and four AUG-like protein-coding genes in lamprey. Of these six genes, only one ALK-like and two AUG-like genes exhibited early embryonic expression that parallels model mammal systems. Two copies of AUG are present in nearly all jawed vertebrates. Our phylogenetic analysis strongly supports the presence of previously unrecognized functional convergences of ALK and LTK between actinopterygians and sarcopterygians-despite contemporaneous, highly conserved synteny of ALK and LTK. These findings provide critical guidance regarding the propriety of fish and mammal models with regard to model organism-based investigation of these medically important genes. In sum, our results provide the phylogenetic context necessary for effective investigations of the functional roles and biology of these critically important receptors.

Automated summary

Comparative genomic analyses are crucial in identifying key genes related to human health, such as those involved in cancer development. The study investigates the evolutionary histories of ALK and LTK genes in different species, revealing functional convergences between actinopterygians and sarcopterygians. These findings offer important insights into the role and biology of these critical receptors, guiding future investigations in model organisms.